[unreadable] Hypoparathyroidism is an uncommon disorder in which parathyroid hormone (PTH) is absent from the circulation. Without PTH, the skeleton does not undergo normal bone turnover, a process that is essential for healthy skeletal remodeling. The focus of my K23 is to test the hypothesis that PTH is essential for normal skeletal structure and function. I am studying bone quality in 30 patients with hypoparathyroidism before and after PTH replacement. My first goal is to characterize thoroughly the skeleton in the hypoparathyroid state. I have made significant progress toward this original goal by performing percutaneous iliac crest bone biopsies on 19 subjects to date with hypoparathyroidism. The preliminary data indicate that bone turnover in hypoparathyroidism is profoundly suppressed and that indices of bone quality are markedly abnormal. The second goal of the K23 is to administer PTH to subjects with hypoparathyroidism and to test how the abnormal properties of bone that were characterized in the PTH-deficient state could be attributed to the lack of PTH. I am currently administering PTH(1-84) to 19 study subjects. The preliminary data suggest that PTH replacement is restoring bone turnover to normal. As the project proceeds, pursuing other aspects of the goals of the project, I expect that concomitant improvements in bone quality will be demonstrable. One area of the original application that was not proposed for study relates to underlying mechanisms that can account for PTH's actions to regulate bone turnover and improve bone quality. One attractive mechanism is that PTH is providing new osteoblasts that become available for enhanced bone remodeling. Recently, it has been observed that osteoblast lineage cells can be detected in significant numbers in the peripheral blood. To expand the research objectives of the K23, I will test the hypothesis that PTH increases the number of circulating osteoblast lineage cells when administered to subjects with hypoparathyroidism. Thus, in addition to continuing to pursue the original goals of the K23 award, I will conduct a pilot study to determine whether hypoparathyroidism is associated with reduced circulating osteoblast lineage cells and whether PTH replacement provides a greater supply of these cells. I expect that the data acquired in this new avenue of research will lead to further studies to delineate more mechanistically how PTH affects osteoblast lineage properties, not only in hypoparathyroidism, but also in primary hyperparathyroidism and after PTH treatment for osteoporosis. This project will continue and extend my ongoing investigation into the actions of parathyroid hormone to improve bone quality. Additional studies are planned to gain new information about an attractive mechanism to account for these observations, namely an effect to increase the availability of osteoblast, or bone-building, cells. [unreadable] [unreadable]